Composition of matter and method of use

ABSTRACT

A composition of matter consisting of sulfamethoxypyridazine or sulfaethoxypyridazine, a bismuth subcarbonate or bismuth subnitrate and ethylcellulose in a sustained release formulation which provides prolonged high sulfonamide blood levels in the treatment of warm-blooded and particularly ruminant animals. A method of using said compositions for controlling bacterial infections is described.

United States Patent 1191 Henderson et a1.

[ COMPOSITION OF MATTER AND METHOD OF USE [75] Inventors: Norman Leo Henderson, Park Ridge, N.J.; August Joseph Bruno, Chester, N.Y.; James Joseph Drain, Trenton, NJ.

[73] Assignee: American Cyanamid Company,

Stamford, Conn.

[22] Filed: Mar. 22, 1971 [21] Appl. No: 127,024

[52] US. Cl 424/22, 424/19, 424/228,

424/229 [51] Int. Cl A6lk 9/00 [58] Field of Search 424/19-22, 228, 229

(56] References Cited UNITED STATES PATENTS 3,535,419 10/1970 Siegrist et al 424/22 1 Sept. 11, 1973 3,507,952 4/1970 Rednick et a1 t. 424/22 3 ,056,724 10/ 1 962 Marston 3,594,469 7/1971 Whitehead et al 424/14 FOREIGN PATENTS OR APPLICATIONS 936,386 9/1963 Great Britain 972,128 10/1964' Great Britain Primary ExaminerShep K. Rose Attorney-Ernest Y. Miller 1 1 ABSTRACT 5 Claims, No Drawings COMPOSITION OF MATTER AND METHOD OF 1 USE PRIOR ART The use of sulfamethazine in cattle has been described by Ellison et al. Journal of the American Veterinary Medical Association 150 No. 6 pp. 629-633, March, 1967.

DESCRIPTION OF THE INVENTION The present invention relates to compositions containing sulfapyridazines, bismuth subcarbonate or bismuth subnitrate and ethylcellulose and method of using the same.

The sulfapyridazines useful in the present invention are those of the formula:

wherein R is methyl or ethyl.

The preparation of the above compounds is described in U. S. Pat. No. 2,712,012.

It is known that sulfa drugs such as sulfapyridazines are useful in combatting bacterial diseases in warmblooded and particularly ruminant animals. To be effective both magnitude and duration of the sulfonamide blood level concentration is of prime importance to successful antibacterial therapy.

It has been found that a formulation comprising from to 40 percent of a rapid release granulation and from 100 to 60 percent of a sustained release granulation wherein the active ingredients are sulfaethoxypyridazine or sulfamethoxypyridazine and high density bismuth subcarbonate or bismuth subnitrate combined with from 2 to 5 percent ethylcellulose, when compressed into dosage unit forms such as OBLETS, tablets etc. provide initially high and prolonged blood levels eminently useful for successful sulfonamide therapy in warm-blooded animals particularly in ruminant animals.

Compositions of the present invention, which in the form of an OBLET provide effective therapy may be specifically prepared as follows: A rapid release granulation, comprising about 90 percent sulfaethoxypyridazine or sulfamethoxypyridazine with excipients such as starch, is prepared with the aid of water as a granulating medium. A sustained release granulation is prepared containing about 60 percent of sulfaethoxypyridazine or sulfamethoxypyridazine, about 37 percent high density (approximately 6.7 g./cc.) bismuth subcarbonate or bismuth subnitrate and about 3 percent ethylcellulose. The latter is granulated with about 75 percent isopropanol, ethanol or chlorinated hydrocarbons. The two granulations are blended to give best results in the proportion of about 25 percent of rapid release with 75 percent of sustained release resulting in having the sulfadrug present in from 62 to 68 percent. Small amounts of lubricant such as magnesium stearate and stearic acid are added to the blend and the material is then screened and compressed into OBLETS. A typical OBLET prepared by such process would be one weighing 23.5 grams with dimensions of 2 inches by thirteen/sixteenths inches and containing 15.0 grams of sulfaethoxypyridazine or sulfamethoxypyridazine, 7.15

grams of high density bismuth subcarbonate or bismuth subnitrate and less than a gram of ethylcellulose.

The purpose of the high density bismuth subcarbonate or bismuth subnitrate is to provide a dosage unit particularly in cattle which will remain in the rumen during the period of release and which will not be excreted by the animal before the sulfaethoxyor sulfamethoxypyridazine has been absorbed into the animals blood stream.

The present invention shows improved results when dosage units contain from about 60 to 72 percent sulfaethoxyor sulfa-methoxypyridazines, 23 to 35 percent heavy density bismuth subcarbonate or bismuth subnitrate and about 2 to 5 percent ethylcellulose. These figures are derived from using compositions consisting of 0 to 40 percent of fast release sulfaethoxyor sulfamethoxypyridazines combined with from 100 to 60 percent of sustained release formulation comprising sulfaethoxyor sulfamethoxypyridazine, heavy density bismuth carbonate or bismuth subnitrate and from 2 to 5 percent ethylcellulose.

SPECIFIC DISCLOSURE The following examples show the preparation of an effective dosage form (OBLET) and the comparative effect of blood levels between the OBLET prepared in accordance with the present invention, OBLETS without sustained release formulation and a leading commercial product (sustained release sulfamethazine).

EXAMPLE 1 PREPARATION OF SUSTAINED RELEASE OBLETS The following formulation is prepared.

Part A (Rapid Release):

sulfaethoxypyridazine (5.131.) 75.0 grams Starch, USP Screened 7.0 grams Starch, Modified 1.8 grams Purified water qs. Part B (Sustained Release):

sulfaethoxypyridazine (S.E.Z.) 225.0 grams Bismuth Subcarbonate, High 143.0 grams Density Ethylcellulose NF (10 cps) I 1.0 grams Isopropanol 75% 96.0 grams EXAMPLE 2 COMPARATIVE BLOOD LEVEL STUDIES Comparative blood level studies are carried out employing the following dosage units:

A. Sulfamethazine sustained release OBLETS,

Norden Labs. (Each contains 22.5 gm. of sulfamethazine) (120 mg./lb.)

B. OBLETS containing 75 percent sustained release and 25 percent fast release granulations (prepared as described in Example 1) mg./1b.)

--A Sulfamethazine formula tion.

---B Sulfaethoxypyridazine --C Sulfaethoxypyridazine (100% sustained release) -D Sulfaethoxypyridazine (100% fast release) Therapeutic level 30 p.p.m.

GRAPH I OBLETS are administered orally to cattle at the indicated doses. The sulfonamide blood level of the individual animals are determined at 3, 6, 12, 24, 36, 48, 60, 72, 96, 120 and I44 hours The relative results ap- 5 pearing in Graph I are as follows:

525 aooqm 5 5m C. OBLETS containing only sustained release sulfaethoxy-pyridazine-bismuth subcarbonate granulation (100 mg./lb.)

D. OBLETS containing only fast release sulfaethoxypyridazine granulation (25 mg./lb.)

60 72 Time in Hours This graph (1) shows the curve A (sulfamethazine formuation) blood levels reached about ppm after about 36 hours and then decreased at a steady rate up to 144 hours. Curve B (compositions of the present invention 75 percent sustained release and percent fast release) shows that sulfonamide blood levels reached a peak of 89 ppm in only 12 hours and then a steady decline up to 144 hours. A composition of this type therefore provides much higher blood levels in a much shorter period of time than curve A. Curve C (100 percent sustained release) showed a slow buildup in sulfonamide blood levels ppm at 36 hours), and as expected, a slow release rate up to 144 hoursCurve D (100 fast release) showed a fast buildup in sulfonamide blood levels ppm at 12 hours) but as expected, the sulfonamide blood levels fell rapidly. The following Table 1 shows the testing results obtained.

EXAMPLE 3 Following the procedure and formulations of Example 1, Parts A and B were granulated separately but not blended together. Instead they were compressed on a standard layering tabletting machine providing layered tablets which compressed about 25 percent rapid release and about percent sustained release material. Results obtained are similar to that of Example 2(B).

ch1 II Average and Range of Su Given S.E.Z.

EXAMPLE 4 In the following tests three calves, each weighing between 300 and 400 pounds, are given 25 mg./1b. of

body weight of sulfaethoxypyridazine. The drug is administered as a single oral dose using the commercial 17.1 gram tablets marketed as S.E.Z. (sulfaethox-.

ypyridazine) OBLETS. These OBLETS have the following analysis:

Sulfaethoxypyridazine Rapid Release Formulation Sull'aethoxypyridazine 15.0 gm. Cornstarch (modified) .5 gm. Cornstarch USP 1.5 gm. Magnesium Stearate USP .09gm. FD and C Red Dye No. 2 .03gm.

.At intervals up to 120 hours following treatment, bloodsamples are taken from each of the animals and sulfonamide determinations made thereon. Results of these From these data it can be seen that utilizing the above procedure sulfonamide blood levels reach therapeutically effective levels in about six hours, peak at about twelve hours and then begin to diminish. These data are also presented in Graph 11 as follows;

onamide Bloodconcentrations in Cattle (Regular) at. 25mg./lb.

(3O p.p.m. therapeutic level) E 9; 90 a g 80- H .p .d :3 70

C U U g 60 D U 8 5 'F r4 an o 10 O 5 9-! H w 20 3 s 12 2 1 36 +8 so 7? as Time in Hours In practice, in order to maintain sulfaethoxypyridazine blood levels above about 30 PPM (therapeutic level) for an extended period, for example, from 3 to 5 days, the drug is administered on a daily basis for the desired period at the above levels (i.e., 25 mg./lb. body weight) A standard calf diet is used throughout the tests and feed and drink is ad libitum.

EXAMPLE 5 For the following tests, sulfaethoxypyridazine is used in three different formulations designed to provide sustained release of sulfaethoxypyridazine over an extended period of about five days. The formulations set forth below are prepared and then compacted as OB- LETS of the same size and shape of those used in Example 4. Nine calves weighing between 300 and 400 lbs. each are selected and randomly placed in one of three treatment groups.

The test OBLETS are given as a single oral dose at 75 mg./lb. of body weight. Blood samples from each calf are taken at intervals up to 120 hours after treatments and all samples are analyzed for sulfaethoxypyridazine. The blood levels for each treatment are given below.

Sustained Release Formulations (No Rapid Release) A B C Sulfaethoxypyridazine 15.00 15.00 15.00 Bismuth subcarbonate 7.05 6.60 6.20 Ethylcellulose N.F. l cps. 0.65 1.10 1.50 Stearic Acid 0.15 0.15 0.15 Magnesium Stearate 0.15 0.15 0.15

Total 23.00 23.00 23.00

% Ethylcellulose (A, 3), (B, 5) and (C, 7).

TABLE 3 Blood Levels Time Post Apparent Sulfaethoxypyridazine Administration, hrs. in Blood, PPM

A B C 3 2.4 1.7 1.05 6 5.9 3.8 2.6 12 9.3 3.2 6.4 24 9.5 7.7 10.8 36 29.8 6.2 5.2 48 24.0 15.4 12.4 60 14.3 11.4 7.8 72 45.8 41.8 16.6 96 21.3 26.7 6.3 120 13.3 15.8 5.3

From these data it can be seen that the 3 and 5 percent ethylcellulose formulations give a sustained release of sulfonamide starting at 36 or 48 hours respectively. The 7 percent ethylcellulose formulation did give sustained release but did not achieve satisfactory sulfonamide blood concentration.

EXAMPLE 6 Marked improvement in the early release of sulfaethoxypyridazine from a sustained release tablet is obtained with the following formulations containing from about to 40 by weight of the rapid release composition of Example 4 and from about 80 to 60 percent by weight of the sustained release composition of formulation A in Example 5.

The ethylcellulose component is related only to the sustained-release granulation; i.e., in preparation of the final'tablet a sustained-release component such as described in Example 1 is physically admixed with a rapid release granulation such as described in Example 5.

In these tests, the OBLETS are prepared and administered to calves as described in Example 4. Blood samples are taken at 3, 6, l2 and 24 hours after treatment and analyzed for sulfaethoxypyridazine. Administra tion was at 100 mg./lb. of body weight for all treatments and data obtained are reported below in Table 4.

Inventive Composition Enhanced early release and improved sustained release of sulfaethoxypyridazine into the blood stream of cattle is evidenced by the following tests wherein test formulations are made up and compacted into OB- LETS of the same size and shape as described in Example 4 (re, 2 inches X 13/16 inches). Formulations prepared are as follows:

A B C Sulfaethoxypyridazine 15.00tg 15 00 15.00 Starch USP 0.35 0.28 0.21 Starch Modified 0.15 0.12 0.09 Bismuth Subcarbonate 7.98 8.05 8.10 Magnesium Stearate 0.15 0.15 0.15 Stearic acid 0.15 0.15 0.15 Ethylcellulose NF. (10 cps) 0.55 0.59 0.62

Formulation (A) is a percent sustained release, 25 percent rapid release formulation, (B) is an /20 formulation and (C) is an /15 formulation. All formulations are prepared to contain 3 percent ethylcellulose in the sustained-release fraction.

The OBLET are administered to calves weighing 300- to 400 lbs. each as a single oral dose mg./lb. of body weight. Six calves per treatment are used and blood samples are taken periodically from each calf following treatment. Data obtained are reported below in Table 5.

TABLE 5 Time Post Apparent Sulfaethoxypyridazine Administration, hrs. in Blood, PPM

A B C 3 17.0 10.0 3.4 6 71.3 39.4 14.2 12 94.0 66.1 49.1 24 81.1 102.1 69.3 36 105.1 109.6 56.8 48 51.3 67.3 62.6 72 26.7 31.9 37.9 96 14.0 15.8 32.3 5.9 5.6 13.6

The above data are compared on Graph 111 with the data of Example 4 obtained with the standard commercial sulfaethoxypyridazine product given as a single oral dose.

GRAPH IV ms..2. 75/25 so s.1-:.z. "/25 EC 1 fi n B r O 0 O 0 O O 0 O O 0 9 8 7 6 5 h 3 2 1 E a a 5 wa e e002 ogEecou zm Time in Hours zine sustained release product (Groups A-D) of Example 8 and an average of the preferred /25 3 percent ethylcellulose formulations of Examples 6 and 7 are made in Graph V.

EXAMPLE 9 A comparison of the data obtained with the rapid re- 35 lease S.E.Z. formulation of Example 4, the sulfametha- GRAPH V 51nd c 326 ocean waded-62am Time in Hours The graph shows that sulfaethoxypyridazine (75/25) reached much higher levels and maintained therapeutic levels or above for at least 60 hours.

We claim:

1. A therapeutic composition of matter having sustained antibacterial activity in ruminant animals consisting essentially of a tablet comprising from 60 to 72 percent Sulfamethoxypyridazine or Sulfaethoxypyridazine, 35 to 23 percent heavy density bismuth subcarbonate or bismuth sub-nitrate effective to provide a dosage unit which will remain in the rumen during the period of release and which will not be excreted before the sulfadrug has been absorbed into the blood stream and 2 to percent ethylcellulose said tablet being formed by mixing separately granulated (I) about 25 percent of a fast release formulation consisting essentially of an immediate initially high effective fast buildup blood level dosage of said sulfadrugs and starch together with (2) about 75 percent of a sustained release formula-tion consisting essentially of an effective slow build-up blood level dosage of said sulfadrugs, about 35 percent said bismuth salts and about 5 percent ethylcellulose.

2. A therapeutic composition of matter in accordance with claim I, essentially containing sulfaethoxypyridazine 66 percent heavy density bismuth subcarbonate 30 percent, and ethylcellulose 3 percent.

3. A theraputic composition of matter in accordance with claim 1, essentially containing sulfaethoxypyridazine 67.5 percent, heavy density bismuth subcarbonate 28.5 percent, and ethylcellulose 3 percent.

4. A therapeutic composition of matter in accordance with claim 1, essentially consisting of from to 72 percent sulfaethoxypyridazine, 35 to 23 percent heavy density bismuth subcarbonate and 2 to 5 percent ethylcellulose.

5. A method of controlling bacterial infections in ruminant animals for an extended period of time comprising the administration to said animals of from about 25 mg. per pound of body weight to about 200 mg. per pound of body weight of the therapeutic composition ofmatter of claim 1. 

2. A therapeutic composition of matter in accordance with claim 1, essentially containing sulfaethoxypyridazine 66 percent heavy density bismuth subcarbonate 30 percent, and ethylcellulose 3 percent.
 3. A theraputic composition of matter in accordance with claim 1, essentially containing sulfaethoxypyridazine 67.5 percent, heavy density bismuth subcarbonate 28.5 percent, and ethylcellulose 3 percent.
 4. A therapeutic composition of matter in accordance with claim 1, essentially consisting of from 60 to 72 percent sulfaethoxypyridazine, 35 to 23 percent heavy density bismuth subcarbonate and 2 to 5 percent ethylcellulose.
 5. A method of controlling bacterial infections in ruminant animals for an extended period of time comprising the administration to said animals of from about 25 mg. per pound of body weight to about 200 mg. per pound of body weight of the therapeutic composition of matter of claim
 1. 